The aim of the present invention is a pulverulent mannitol with a fine particle size, high density and excellent flow capability, and also having a high mannitol content and rapid rate of dissolution In water.
The invention also concerns a process for manufacturing the said mannitol as well as its use in the fields of pharmaceuticals and foodstuffs.
The pharmaceutical and foodstuffs industries consume large amounts of pulverulent polyols as excipients, bulk sweeteners or as carriers for additives. More precisely this involves sorbitol, xylitol, mannitol and maltitol.
Sorbitol has the advantage of being the least expensive product among these three polyols, which explains the fact that it is used very often. Nevertheless, as soon as any re-uptake of water has occurred, its high hygroscopicity leads to a product whose flow is difficult or even impossible.
To avoid this problem, a sorbitol with a coarser particle size is chosen, but then the time taken to dissolve in water generally becomes excessively long. In addition, the highly hygroscopic nature of sorbitol renders any use of this polyol out of the question when it is associated with active principles or ingredients that are very sensitive to water.
With regard to xylitol, this is scarcely ever used as an excipient because it has the disadvantage of caking under conditions of normal humidity, and does so even more readily than sorbitol.
Because of its low hygroscopicity, mannitol could be an excellent excipient since it is compatible with the majority of active ingredients, but unfortunately the product obtained by crystallisation in water beginning with a supersaturated solution has mediocre flow properties.
In fact, crystalline mannitol is excessively friable, leading to the formation of fine particles that are particularly detrimental to its flow properties.
In addition, because of its compact crystal structure, mannitol obtained by crystallisation in water has a poor ability to dissolve. This slow dissolution rate, although it can be an advantage in certain special applications, is always considered to be a major disadvantage in the cases that are of interest here, which hinders its use.
Other pulverulent forms of mannitol together with the means for obtaining the latter are described in the literature.
For example U.S. Pat. No. 3,341,415 deals with a method for preparing a pharmaceutical excipient containing at least 20% by weight of mannitol and an additional sugar chosen from among lactose, saccharose, erythritol, galactose and sorbitol. However, the process described is very tricky to operate on an industrial scale. Moreover, the product obtained is highly hygroscopic, very compact and very difficult to dissolve in water.
The patent application JP 61.85330 relates to a process for preparing excipients characterized by the fact that it consists of drying D-mannitol by spray atomization. However, it appears that the products obtained in this way contain more than 50% of particles smaller than 75 xcexcm, which is detrimental to the correct flow of the product.
U.S. Pat. No. 3,145,146 describes a process for modifying the physical properties of mannitol by spray-drying, and the product thus obtained.
A powder whose particle size lies between 5 and 100 xcexcm is obtained. However, this process consists of adding a binder, which can be a paraffin, a gum or a cellulose derivative, before the spray-atomization stage. In addition, at least 50% of the powder particles still have a size smaller than 75 xcexcm, which is far from being ideal to obtain good flow.
All of the above shows that there is an unsatisfied need to have available a mannitol for use as an excipient that has a fine particle size, a high density and an excellent flow ability, it being advantageous for these properties to be combined with a high mannitol content and a rapid rate of dissolution in water.
Furthermore, in order for this excipient to be preferred for use as a powder to fill hard capsules, it has been found that it is necessary to have a product that will be compatible with the active ingredient with which it is associated, and that its free-flowing properties, homogeneity of mixing, dissolution profile and packed density conform to the required application.
To obtain an excipient of this kind having all the functional properties listed above, the applicant company has discovered that, contrary to all expectation, it is advisable to choose from among the polyols a pure crystalline mannitol and to modify its physical properties by using a suitable process such that it has at the same time a fine particle size, a high density and excellent flow capability, and in addition a high mannitol content and a rapid speed of dissolution in water.
Thus the applicant company has distinguished itself by reconciling all of these aims that were up to this time supposed to be irreconcilable, by devising and developing, through numerous investigations, a novel pulverulent mannitol.
Thus the invention relates to a pulverulent mannitol characterized in that it has:
an average diameter of between 60 and 200 xcexcm, preferably being between 80 and 180 xcexcm,
a packed density, determined according to a Test A, of between 0.65 and 0.85 g/ml, preferably between 0.7 and 0.8 g/ml,
a flow factor of at least 60, preferably between 60 and 90.
The pulverulent mannitol according to the invention has an average diameter of between 60 and 200 xcexcm, preferably between 80 and 180 xcexcm. These values are determined on a COULTER(copyright) LASER LS granulometer by determining the volume size distribution of the particles of pulverulent mannitol.
Thus the size of the component particles of the pulverulent mannitol according to the invention enables it to maintain an average diameter relative to that of the majority of active ingredients and thus to obtain homogeneous mixtures of active ingredients with mannitol by granulometric (particle size) equivalence.
In fact, it has been found quite generally that an elevated active ingredient crystal size impairs their dissolution speed. Therefore an average diameter of between 80 and 200 xcexcm is recommended.
The pulverulent mannitol according to the invention can also be characterized by its packed density.
The determination of the packed density is carried out according to the method specified in the operating instructions for the HOSOKAWA P.T.N. powder tester.
Under these conditions, the pulverulent mannitol according to the invention has a high packed density, i.e. comprised between 0.65 and 0.85 g/ml, and preferably comprised between 0.7 and 0.8 g/ml.
This high density value gives the pulverulent mannitol according to the invention properties that are particularly appropriate to its use as a filling agent for small hard capsules in pharmacology, namely a size that is more acceptable by patients.
In addition, the pulverulent mannitol according to the invention can also be characterized by its flowability, this property being especially appropriate when the said mannitol is used to fill hard capsules.
The ability of the said mannitol to flow is measured using the POWDER TESTER instrument marketed by the HOSOKAWA Company. This equipment enables the ability of a powder to flow to be measured under standardised, reproducible conditions and the calculation of a flow factor, also called the Carr Index.
The pulverulent mannitol according to the invention has an excellent flow factor, generally at least 60 and preferably of between 60 and 90.
This value is generally much better than that of the crystalline mannitol powders of the prior art, and is equivalent to mannitol powders obtained by extrusion or atomisation processes.
However, the products obtained by extrusion usually have a large particle size with an average diameter of between 250 and 600 xcexcm, and those obtained by atomisation typically have a low packed density, less than 0.6 g/ml, which makes these two categories of product particularly poorly suited to the required areas of application.
The pulverulent mannitol according to the invention is characterised in that it also has a mannitol content at least equal to 96% by weight, preferably at least equal to 98% by weight.
Thus from the point of view of its chemical composition, the pulverulent mannitol according to the invention is relatively pure.
Thus it is surprising and unexpected that a pulverulent mannitol that already has such an ability to flow with a fine particle size and such a packed density simultaneously has such a high chemical purity.
In fact, as far as the applicant company knows, the only pulverulent mannitols that have good flowability comprise, as mentioned above, binders such as paraffin, gums or cellulose derivatives.
Finally, the pulverulent mannitol according to the invention is characterised by its rapid rate of dissolution in water, this rate being measured according to Test B developed by the applicant company.
To measure the speed of dissolution in water according to Test B, exactly 5 g of the product to be tested is put into 150 ml of deionised, degassed water maintained at 20xc2x0 C. and stirred at the rate of 200 rpm.
The dissolution speed corresponds to the time needed, after introducing the product, to visually obtain perfect clarity of the suspension prepared in this way.
Under these conditions the pulverulent mannitol according to the invention has a rapid dissolution rate, i.e. of between 20 and 60 seconds. These dissolution rates are generally well suited to the intended applications.
The pulverulent mannitol according to the invention can be obtained by carrying out a mannitol powder granulation step by a wet method using a binder, followed by a maturing stage by drying the pulverulent mannitol thus obtained.
To obtain a pulverulent mannitol according to the invention and having the stated functional characteristics, the applicant company has discovered that it is appropriate to choose as a starting material mannitol a mannitol powder that can be obtained by crystallisation in water or in some other solvent such as alcohol.
The particle size of the said mannitol powder starting material does not in itself constitute a limiting factor for the production of a pulverulent mannitol according to the invention.
With regard to the binder, this consists of water or a mannitol syrup with a dry material content equal to at most 50% and preferably of between 20 and 40%, or even water vapour (steam) as will be exemplified below.
In a surprising and unexpected way, the applicant company has discovered that the granulation of a mannitol powder by a wet method using a binder enables the preparation in high yield of a product in accordance with the invention as far as its particle size, density and flowability are concerned.
In fact, the processes described in the past do not allow the totality of the desired characteristics to be obtained.
To carry out the granulation, it is possible to use for example a continuous mixer-granulator of the vertical FLEXOMIX type marketed by the HOSOKAWA SCHUGI company or the horizontal CB type marketed by the Lxc3x96DIGE company, into which the mannitol powder starting material to be granulated is introduced continuously via a weight dispensing device, and into which the binder (water, water vapour (steam) or the mannitol solution) is introduced continuously via a volumetric dispensing device. The granulation can also be carried out in a spray atomising tower or in a fluidised bed granulator.
Preferably a continuous mixer-granulator of the vertical HOSOKAWA SCHUGI FLEXOMIX type is chosen for use. The mannitol powder starting material and the binder are mixed very intimately in the mixer-granulator which is equipped with a shaft with knives arranged as blades and a system for atomising liquids by injection nozzles.
In a preferred mode of the process, good dispersion of the constituents and the agglomeration of the particles of mannitol powder starting material are achieved by mixing at high speed, i.e. at a value equal to at least 2000 rpm, preferably equal to at lease 3000 rpm. At the outlet of the mixer-granulator, the granules formed are discharged continuously onto a dryer. The discharge preferably takes place by gravity in the case of the said vertical granulator, and by thrust, via the shaft of the rotating knives if the horizontal granulator is used.
This second stage of drying at the outlet of the mixer-granulator enables the water originating from the binder to be removed and the crystallisation of the dry material originating from the binder in the case where a mannitol solution was used, in such a way that the crystallisation takes place after the foregoing granulation stage. The dryer can be, for example, a fluidised bed dryer or a rotary maturing drum.
The pulverulent mannitol according to the invention is obtained after cooling and optionally sieving. In this case, the fine particles can be recycled directly to the start of the granulation, and the coarse particles can be crushed/ground and recycled to the input of the screening or to the input of the granulation.